MOLECULAR MARKERS IN ESOPHAGEAL ADENOCARCINOMA

肿瘤抑制基因位点的多染色体等位基因缺失和遗传改变已被报道在食管腺癌中。我们在之前的相关研究E3293和E1294中已经表明，18q染色体缺失是结肠癌术后辅助化疗患者的不良预测指标。化疗药物诱导细胞凋亡，因此，理论上，细胞凋亡、复制和细胞周期调节的改变可能影响治疗反应。本提案的目的是解决在食管远端和食管胃连接处（EGJ）的腺癌患者中，我们关于结肠癌染色体18q缺失的发现，并开发其他新的线索，研究遗传改变对术后辅助治疗的预后影响。我们建议评估遗传改变作为食管癌化疗反应预测标志物的两个假设：1。18q染色体的等位基因缺失会导致术后辅助治疗后的生存率下降。2. 完整的凋亡、DNA合成和细胞周期控制通路将导致术后辅助化疗后更好的生存。为了解决第一个假设，特异性目标1是在东部肿瘤合作组（ECOG）的E8296临床试验中表征食管癌和EGJ腺癌中18q等位基因丢失的特征，并将结果与生存率联系起来。我们将利用一组微卫星标记，通过聚合酶链反应扩增来自肿瘤常规组织学切片的DNA，来评估18q等位基因的丢失。生存分析将由ECOG统计中心进行。对于第二个假设，特异性目标2是表征凋亡、DNA合成和细胞周期控制途径，并将结果与存活联系起来。我们将使用免疫组织化学方法对抗体（bcl2、bclxL、bax、p53、p21WAF1、p27Kip1、cyclinD1、Ki-67）和等位基因丢失（染色体17p）进行检测，以确定这些途径的特征，并将这些发现与生存率联系起来。本研究将为18q等位基因缺失作为食管癌术后辅助化疗患者的预测指标提供重要信息。该研究还将指导未来的凋亡，DNA合成和细胞周期控制途径作为合作群体设置的标记的研究。

Multiple chromosomal allelic losses in tumor suppressor gene loci and genetic alterations have been reported in esophageal adenocarcinomas. We have shown in previous correlative studies E3293 and E1294 that loss of chromosome 18q is an adverse predictive marker for patients with colon cancer treated with postoperative adjuvant chemotherapy. Chemotherapeutic agents induce apoptosis, and, therefore, in theory, alterations in apoptosis, replication and cell cycle regulation may affect therapeutic response. The goals of this proposal are to address in patients with adenocarcinoma in the distal esophagus and esophagogastric junction (EGJ) our findings on chromosome 18q loss in colon cancer and to develop additional new leads to the genetic alterations with prognostic implications for post-operative adjuvant therapy. We propose to evaluate two hypotheses addressed at genetic alterations as predictive markers for chemotherapeutic response in esophageal adenocarcinomas: 1. Allelic loss of chromosome 18q will lead to worse survival after post- operative adjuvant therapy. 2. Intact apoptotic, DNA synthetic, and cell cycle control pathways will result in better survival after post-operative adjuvant chemotherapy. To address the first hypotheses, Specific Aim number 1 is to characterize allelic loss of 18q in esophageal and EGJ adenocarcinomas in clinical trial E8296 of the Eastern Cooperative Oncology Group (ECOG) and correlate the results with survival. We will assess 18q allelic loss with a panel of microsatellite markers by polymerase chain reaction amplication of DNA from routine histological sections of tumors. Survival analyses will be carried out by the ECOG Statistical Center. For the second hypothesis, Specific Aim number 2 is to characterize apoptotic, DNA synthetic and cell cycle control pathways and correlate the results with survival. We will use immunohistochemistry with a panel of antibodies (bcl2, bclxL, bax, p53, p21WAF1, p27Kip1, cyclinD1, Ki-67) and allelic loss (chromosome 17p) to characterize the pathways and correlate the findings with survival. This study will provide important information about the potential utility of chromosome 18q allelic loss as a predictive marker in patients with esophageal adenocarcinoma treated with postoperative adjuvant chemotherapy. The study will also direct future studies of apoptotic, DNA synthetic, and cell cycle control pathways as markers in the cooperative group setting.